Dietary Obesity-associated Hif1α Activation in Adipocytes Restricts Fatty Acid Oxidation and Energy Expenditure Via Suppression of the Sirt2-NAD+ System

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2012 Feb 4

PMID 22302938

Citations 165

Authors

Jaya Krishnan

Carsten Danzer

Tatiana Simka

Josef Ukropec

Katharina Manuela Walter

Susann Kumpf

Peter Mirtschink

Barbara Ukropcova

Daniela Gasperikova

Thierry Pedrazzini

Wilhelm Krek

Affiliations

Soon will be listed here.

Abstract

Dietary obesity is a major factor in the development of type 2 diabetes and is associated with intra-adipose tissue hypoxia and activation of hypoxia-inducible factor 1α (HIF1α). Here we report that, in mice, Hif1α activation in visceral white adipocytes is critical to maintain dietary obesity and associated pathologies, including glucose intolerance, insulin resistance, and cardiomyopathy. This function of Hif1α is linked to its capacity to suppress β-oxidation, in part, through transcriptional repression of sirtuin 2 (Sirt2) NAD(+)-dependent deacetylase. Reduced Sirt2 function directly translates into diminished deacetylation of PPARγ coactivator 1α (Pgc1α) and expression of β-oxidation and mitochondrial genes. Importantly, visceral adipose tissue from human obese subjects is characterized by high levels of HIF1α and low levels of SIRT2. Thus, by negatively regulating the Sirt2-Pgc1α regulatory axis, Hif1α negates adipocyte-intrinsic pathways of fatty acid catabolism, thereby creating a metabolic state supporting the development of obesity.

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